BBSRC Project to grow a functional nervous system

BBSRC supported project starting in 2009

Summary

Complex adult nervous systems contain billions of neurons but, are the sophisticated recognition processes allowing eyes to map to the brain or motor nerves to reach the right muscle required when embryonic nervous systems first form? In the very simple spinal cord of the young frog tadpole detailed information on the different types of neurons show they make rather imprecise connections based on where the axons and dendrites which make and receive synapses are located geographically. We build an axon growth model to ask whether very simple developmental rules can control axon growth accurately enough to allow the network controlling tadpole swimming responses to self-assemble. We evaluate this model by mapping the connectome it generates onto a functional model and showing that it can “swim” when stimulated. The results imply that at early stages of CNS development, very simple rules may lay out the first functional networks in the brain.

Introduction to the tadpole and its behaviour

When the tadpole hatches after two days of development, it swims when touched on the tail and continues until it bumps into the side of the dish:

Details of the tadpole response to touch on the head can be seen using high-speed video at 150fps. It flexes to one side and swims away:

These are the swimming responses which we hoped to understand. What are the networks of neurons producing swimming and how do they develop?

The tadpole nervous system

The nervous system of the hatchling Xenopus tadpole is very small and simple. (A) side view of the head shows the eye and below it the black, mucus secreting, cement gland. The networks generating swimming lie in the hindbrain and spinal cord. (B) The spinal cord is a thick walled tube with nerve cells and their axons on the outside:

Since there are not connections across the top of the spinal cord, we can make it nearly 2-dimensional by cutting along the top (dotted line) and opening the nervous system like a book.

Diagram of the tadpole nervous system opened like a book

Before the project started we had a rather detailed picture of the neurons controlling the simple behaviour of the newly hatched Xenopus tadpole. Some of this knowledge can be summarised in a diagram.

Simplified and incomplete diagram shows the main groups of neurons (circles colour coded by the transmitter released) that present evidence suggests may control the tadpole's behaviour.

On the left of the diagram are the stimuli that start swimming. (dim light, touch, noxious substance). On the right are the stimuli that stop swimming (pressure).

Circles are groups of neurons colour coded by the transmitter they release (ascending interneurons are not included). Blobs and triangles are inhibitory and excitatory synapses.

Swimming can be initiated by:

Touching the skin which excites Rohon- Beard (RB) neurons in the trunk or trigeminal touch (Tt) neurons in the head. In the spinal cord Rohon- Beard neurons excite sensory interneurons (dorsolateral (dl) and dorsolateral commissural (dlc)). Excitation then travels to the neurons of the central pattern generator for swimming (white boxes on either side).

The central pattern generator for swimming consistes of descending (d) and commissural (c) interneurons, and motoneurons (mn). During swimming these neurons all fire a single action potential on each cycle of swimming. The alternation of activity is organised by glycinergic inhibition from commissural interneurons. After initiation, swimming activity is sustained by positive feedback excitation from glutamatergic descending interneurons and cholinergic motoneurons.

Swimming normally stops when the tadpole bumps into solid objects and adheres with mucus secreted by a cement gland on the front of the head. Bumping the head skin or cement gland excites trigeminal pressure (Tp) receptors which excite GABAergic midhindbrain reticulospinal (ri) neurons. These project into the spinal cord to inhibit the central pattern generator neurons and terminate swimming.